Social behavior is evolutionarily conserved and highly stereotypic. Emission and detection of specialized chemosensory odorants appropriately regulates mouse social behavior through primary circuits that stimulate the amygdala and hypothalamus. Though chemosensory ligands are not thought to regulate human behavior, studies from stroke and trauma victims have revealed that the same subnuclei within the amygdala and hypothalamus that are activated by chemosensory ligands in the mouse function in humans to similarly generate social behavior. The precise subsets of neurons that generate stereotyped behavior are unknown in any species. We have now identified a protein family of 31 chemosensory ligands that promote stereotypic behavior. The objective of this research is to use this natural toolbox of chemosensory ligands to identify sensory receptors and neural circuits that generate stereotyped behavior. We will systematically manipulate, study, and mutate individuals of this large family of chemosensory ligands to comparatively test, evaluate, and advance our understanding of the organization of the sensory neurons, neural circuits, and central nuclei that generate behavior. 1) We will use calcium imaging to isolate specific neurons that detect these ligands and molecular analysis to identify candidate sensory receptors. 2) We will analyze and compare cFos activity in the brain following exposure each of our 31 ligands in order to identify the neural code associated with each ligand. 3) We will mutate our ligands through the generation of chimeras and rational protein design to selectively activate subsets of sensory neurons and investigate their ability to generate behavior. We expect that at the completion of these aims we will have made important steps towards elucidating the neuronal code that initiates innate behavior and enable us to define at the cellular and molecular level, underlying mechanisms of neural function and dysfunction. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because studies of the neural function that generates stereotyped behavior are expected to reveal evolutionarily conserved mechanisms that will ultimately increase our understanding of the generation of stereotyped behavior in humans. Thus, the proposed research is relevant to the NIH's mission to understand neural function in order to ultimately treat dysfunction such as schizophrenia and autism disorders.